Release of therapeutically active agents in the colon from a perorally administered dosage form is desirable in several situations, including: (1) topical treatment of diseases of the colon such as constipation, irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, carcinomas, and infection in which systemic absorption of the therapeutic agent is neither required or desired; (2) systemic absorption of therapeutic agents such as peptides and proteins which are subject to lumenal degradation in the stomach and small intestine; and (3) systemic absorption of therapeutic agents for which peak systemic concentrations and pharmacological activity are desired at time significantly delayed from the time of peroral administration (i.e., peak plasma concentrations in the early morning just prior to arising, from a peroral dosage form ingested at bedtime). Colonic release of therapeutically active agents from a perorally administered dosage form requires that release of said agent for topical activity or systemic absorption be prevented in the stomach and small intestine, but permitted in the colon. This in turn requires design of the dosage form to be such that it takes advantage of features of the gastrointestinal tract that indicate arrival of the dosage form in the colon, relative to other portions of the gastrointestinal tract (M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2:241-258). Variable features include pH, ionic strength, apparent velocity, and bacterial content of the lumenal contents of the several anatomical portions of the gastrointestinal tract as well as the residence time of a pharmaceutical unit dosage form therein (M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2:241-258; S. S. Davis, J. Contr. Rel., 1985, 2:27-38).
The residence time of pharmaceutical unit dosage forms in the stomach can be particularly variable (M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2:241-258). However, the small intestinal transit time of pharmaceutical unit dosage forms has been demonstrated to be relatively constant with a mean value of approximately three hours (M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2:241-258). Residence times in the colon are usually longer than in other portions of the gastrointestinal tract, but times within the several segments can be highly variable (M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2:241-258).
The pH profile of the lumenal contents of the gastrointestinal tract has also been characterized and found to be relatively consistent (D. F. Evans, G. Pye, R. Bramley, A. G. Clark, and T. J. Dyson, Gut, 1988, 29:1035-1041). The pH of the stomach may vary temporarily with prandial state, but is generally below about pH 2. The pH of the small intestine gradually increases from about 5 to 5.5 in the duodenal bulb to about 7.2 in the distal portions of the small intestine (ileum). The pH drops significantly at the ileocecal junction to about 6.3 and very gradually increases to about 7 in the left or descending colon.
A distinguishing feature of the colon relative to other portions of the gastrointestinal tract is the presence of exogenous bacteria. These are capable of enzymatically catalyzing reactions of which the host animal is incapable.
It has been recognized in general that dosage forms designed for colonic release may employ one of the following features to indicate arrival of the dosage form in the colon, relative to other portions of the gastrointestinal tract: (1) the generally increasing pH profile of the lumenal contents up to the ileocecal junction; (2) the relatively constant small intestinal transit time of a pharmaceutical unit dosage form (compensating for the highly variable stomach residence time); and (3) the presence of exogenous bacteria in the colon (M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2:241-258).
Dosage forms employing the generally increasing pH profile of the lumenal contents of the gastrointestinal tract as a design feature to indicate colonic arrival typically employ film coatings of enteric polymers. These enteric polymers are polyanionic polymers which are insoluble in water and at low pHs, but begin to dissolve at pHs of about 5. Commercially available enteric polymers begin to dissolve within the pH range of about 5 to 7.
The following references use this type of rationale to design dosage forms for delivery to the colon. U.S. Pat. No. 5,171,580, issued Dec. 15, 1992, Boehringer Ingelheim Italia, teaches a preparation for delivery in the large intestine and especially the colon, comprising an active containing core coated with three protection layers of coatings having different solubility. The inner layer is Eudragit.RTM. S, with a coating thickness of about 40-120 microns, the intermediate coating layer is a swellable polymer with a coating thickness of about 40-120 microns, and the outer layer is cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, hydroxyethyl cellulose phthalate, cellulose acetate tetrahydrophthalate, or Eudragit.RTM.L. In the dosage forms of the present invention Eudragit.RTM.S is only used as an outer layer.
U.S. Pat. No. 4,910,021, issued on Mar. 20, 1990, Scherer Corp., teaches a targeted delivery system wherein the composition comprises a hard or soft gelatin capsule containing an active ingredient such as insulin and an absorption promoter. The capsule is coated with a film forming composition being sufficiently soluble at a pH above 7 as to be capable of permitting the erosion or dissolution of said capsule. The film forming composition is preferably a mixture of Eudragit.RTM.L, Eudragit.RTM.RS, and Eudragit.RTM.S at specific ratios to provide solubility above a pH of 7.
U.S. Pat. No. 4,432,966, issued on Feb. 21, 1984, Roussel-UCLAF, teaches a compressed tablet with an active agent, coated with a first coating layer comprising a mixture of microcrystalline cellulose and lower alkyl ether of a cellulose film-forming organic polymer such as ethyl cellulose, and a second coating layer selected from cellulose acetylphthalate, hydroxypropyl methylcellulose phthalate, benzophenyl salicylate, cellulose acetosuccinate, copolymers of styrene and of maleic acid, formulated gelatin, salol, keratin, stearic acid, myristic acid, gluten, acrylic and methacrylic resins, and copolymers of maleic acid and phthalic acid derivatives.
Using pH as an indicator of colonic arrival of the dosage form presents some difficulties. Although the pH of the lumenal contents gradually increases from the stomach through the small intestine, the pH of the lumenal contents of the proximal portions of the colon is lower than that of the distal small intestine (ileum). This is due to the presence of short chain fatty acids produced by the action of exogenous bacteria in the colon. Therefore, a given pH value does not distinguish the colon from various portions of the small intestine. A dosage form designed to release the therapeutic agent at the pH of the proximal colon would also release the therapeutic agent at those portions of the small intestine proximal to the ileum within which the pH is similar to that of the proximal colon. Thus, the validity of the use of enteric coatings to attain colonic release has been questioned (M. Ashford and J. T. Fell, J. Drug Targeting, 1994, 2:241-258; M. Ashford, J. T. Fell, D. Attwood, and P. J. Woodhead, Int. J. Pharm., 1993, 91:241-245; M. Ashford, J. T. Fell, D. Attwood, H. L. Sharma, and P. J. Woodhead, Int. J. Pharm., 1993, 95:193-199)
Although lumenal content pH alone does not distinguish the colon from various other portions of the small intestine, pH does distinguish the stomach from the small intestine and colon. Enteric polymer coatings have been extensively used in the prior art to distinguish the stomach from the small intestine and prevent release of a therapeutic agent until the dosage form has emptied from the stomach. This use has resulted in an extensive history confirming the safety of these polymers, a large literature describing suitable processes for application of these polymers as coatings to dosage forms, and the commercial availability of a number of suitable enteric polymers.
It has been recognized that dosage forms that delay release of a therapeutic agent for a time period corresponding to the stomach and small intestine residence times will provide colonic delivery (S. S. Davis, J. Contr. Rel., 1985, 2:27-38). This has been primarily based upon the reasonably constant residence time in the small intestine, assuming that the additional use of an enteric polymeric coating will compensate for variable stomach residence times by preventing activation of the time based delay mechanism until the dosage form has reached the small intestine. Proposed time delay mechanisms have been based upon slow dissolution of pH independent coatings (A. Gazzaniga, P. Iamartino, G. Maffione, and M. E. Sangalli, Proceed. 6th Int. Conf. on Pharm. Techn. (Paris) 305-313, 1992), controlled pH independent, permeation of water through a coating to activate disintegration of the dosage form by osmotic pressure (F. Theeuwes, P. L. Wong, T. L. Burkoth, and D. A. Fox, in Colonic Drug Absorption and Metabolism, P. R. Bieck, ed., Marcel Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993)) or by physical swelling (R. Ishino, H. Yoshino, Y. Kirakawa, and K. Noda, Chem. Pharm. Bull., 1992, 40:3036-3041), or swelling and ejection of a plug by pH independent hydration (I. R. Wilding, S. S. Davis, M. Bakhshaee, H. N. E. Stevens, R. A. Sparrow, and J. Brennan, Pharm. Res., 1992, 9:654-657). Such approaches have not been completely satisfactory for reasons of size, reproducibility of time to release, complexity, and expense.
Although enteric polymers have a long history of commercial use and inherently compensate for variable stomach residence times, their use to provide a time based delay in therapeutic agent release based upon dissolution of an enteric polymer coating has not been advocated. This is presumably due to the variability in enteric polymer dissolution as a function of the varying pH and velocity of the lumenal contents of the small intestine and colon. However, a dosage form employing an enteric polymer to achieve colonic release based upon dissolution time of the enteric polymer coating has advantages in terms of proven safety of these polymers and commercially feasible application processes.
It is an object of the present invention to provide colonic release of therapeutic agents from a unit dosage form by employing distinct, multiple coatings or layers of enteric polymers as the means of delaying release of the therapeutic agent until the dosage form has reached the proximal colon.